Direct Synthesis of 2-Hydroxytrifluoroethylacetophenones via Organophotoredox-Mediated Net-Neutral Radical/Polar Crossover

Alkene difunctionalization is a very attractive tool in synthetic organic chemistry. Herein, we disclose an operationally and practically simple method to access 2-hydroxytrifluoroethylacetophenones from styrene derivatives via photoredox catalysis. This light-mediated transformation promotes the generation of the 1-hydroxy-2,2,2-trifluoroethyl carbon-centered radical as key synthon, which undergoes Giese addition with styrenes followed by a Kornblum oxidation process. The presented method is not only mild and cost-effective, but also utilizes an organic photocatalyst and DMSO as oxidant. Experimental investigations support the operative mechanism via net-neutral radical/polar crossover.


■ INTRODUCTION
Alkene difunctionalization is generally used to introduce two functional groups in an olefin simultaneously and build complex molecular organic skeletons in a single step.Specifically, transition-metal catalyzed 1 and photoredox 2 approaches have shown their potential for successful 1,2difunctionalization reactions.Typically, this process involves the installation of two functional groups across an olefin to generate C−C and C−Z (Z = C, O, N, S or halogen) bonds, allowing prompt formation of elaborated organic skeletons.
Fluorine is one of the most important heteroatoms in pharmaceuticals both as a single atom or within a functional group, constituting a fundamental element in medicinal chemists' toolbox. 3Thus, routine incorporation of such halogenated moieties has been long studied in new drug design programs.The presence of fluorine or fluorinated groups in a bioactive molecule can provide better metabolic stability, lipophilicity, and binding selectivity. 4Undoubtedly, the trifluoromethyl group is widely prevalent in many agrochemicals and pharmaceuticals, 5 and extensive attention has been devoted toward the design and development of efficient synthetic methods to provide access to CF 3 -containing organic architectures.In recent years, developments in radical, 6 nucleophilic 7 and electrophilic 8 approaches have advanced in the field using CF 3 I, Langlois, Ruppert−Prakash, Togni, Umemoto reagents, and others.
Among different fluorine-containing molecules, secondary trifluoromethyl alcohols are a particular and interesting subset of trifluoromethylated molecules that have relevant applications in medicinal and biological chemistry (Scheme 1A). 9 For example, Befloxatone, antitumor agent Z and Efavirenz are representative examples of bioactive molecules containing such functionality (Scheme 1A). 10 Typically, accessing hydroxytrifluoroethylated compounds relies on the use of the Ruppert-Prakash 11a (TMSCF 3 ) reagent, trifluoroacetaldehyde ethyl hemiacetal, 11b among others.7b Additionally, these molecules can be accessed by direct reduction of trifluoroacetates. 12owever, these routes require cryogenic temperatures and present low functional group tolerance.Given the importance of this functional group, the development of synthetic methods for the direct installation of hydroxytrifluoroethyl group in organic molecules have been recently explored, where single electron transfer (SET) approaches have opened a new avenue for the selective introduction of such moieties. 13ecently, N-trifluoroethoxyphthalimide 1a (Scheme 1B) as redox-active ether has proved to be an efficient and versatile reagent for organic synthesis.First, Aggarwal presented that upon reductive conditions and in the presence of suitable hydrogen donors, reagent 1a provides the oxygen-centered radical I (Scheme 1B), which performs a hydrogen atom transfer (HAT) process on unactivated Csp 3 −H bonds. 14ater on, different research groups have shown that radical I generated from 1a can undergo intramolecular 1,2-HAT to produce the synthetically useful carbon-centered radical II. 13or instance, in 2022 a nickel-catalyzed reductive crosselectrophile coupling between redox-active ether 1a and haloarenes was reported, where the 1,2-HAT event from I to II is the key step for the synthesis of α-aryl-α-trifluoromethyl alcohols. 15Furthermore, 1a can efficiently produce the carboncentered radical II under photochemical conditions. 16Overall, these methods employing reagent 1a have shown their efficiency toward the generation of the carbon-centered radical II via 1,2-HAT, although to date their application is limited to the synthesis of α-(hetero)aryl-α-trifluoromethyl alcohols.Thus, the exploration of additional organic frames for accommodating radical II beyond (hetero)arenes is highly desirable since it would lead to the expedition of new chemical space in organofluorine settings.
Inspired by visible-light promoted preparation of ketones using redox-active species and alkenes, 17 we decided to explore the photochemical generation of radical II and subsequent addition to styrenes.This reaction features both radical and ionic modes of reactivity.The success of this design involves addressing several challenges, from the N−O bond cleavage of 1a via SET to trigger the single electron reduction and oxidation processes along with the 1,2-HAT event.All these processes must be thrived in a controlled and well-orchestrated manner (Scheme 1C), via photoinduced net-neutral radical polar crossover (RPC).2b Interestingly, this reaction will provide access to a prominent variety of 2-hydroxytrifluoroethylacetophenones in a single step from readily available reagents and mild reaction conditions.Of note, access to β-CF 3 -enones from 2-hydroxytrifluoroethylacetophenones is feasible upon dehydration conditions. 18

■ RESULTS AND DISCUSSION
First, the selection of the photocatalyst (PC) to trigger this reaction governed by oxidative quenching photoredox conditions is critical.Thus, we studied the electrochemical properties of fluorinated reagent 1a (E c = −1.63V vs Fc + /Fc, see Scheme 2A) 19 and the model styrene substrate 2a (E a = 0.81 V vs Fc + /Fc).With these results in hand, we selected the highly reducing Ir(ppy) 3 with E 1/2 = −2.45V vs Fc + /Fc Scheme 2A, 19 (see Figure S3 in the Supporting Information) as a potential candidate capable of reducing reagent 1a.To our delight, we observed the product formation (3) in 64% yield (Table 1, entry 1) under 427 nm Kessil light irradiation for 24 h and using an excess of radical precursor 1a (2.0 equiv).Remarkably, the use of DMSO is displaying a good ability to perform the 1,2-HAT process.To date, synthetic methods where a 1,2-HAT event occurs from 1 have been effective only in dimethylacetamide (DMA) or MeOH.The formation of trifluoroacetaldehyde-hydrate as main side product was detected by 19 F NMR.In our case, (Ir((dF)(CF 3 )ppy) 2 (dtbpy))PF 6 did not provide better results (Table 1, entry 2), which proved to be suitable in previous photoinduced methods employing reagent 1a. 13 Attempts to use organophotocatalysts (Table 1, entries 3−4) only furnished the desired acetophenone derivative 3 when using 1,3-dicyano-2,4,5,6-tetrakis(diphenylamino)-benzene (4DPAIPN) (E 1/2 = −1.99V vs Fc + /Fc).Although organic 1,2,3,5-tetrakis-(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) may thermodynamically reduce 1a it can also oxidize styrene 2a, thus allowing a competition between oxidative and reductive quenching pathways.No differences were observed between Ir(ppy) 3 and 4DPAIPN, thus we decided to continue with the more accessible organic PC.Lowering or increasing loadings of 4DPAIPN resulted in less efficacy (Table 1, entries 5−6).Interestingly, more energetic wavelength (Table 1, entry 7) resulted in the formation of complex reaction mixtures and product decomposition.In contrast, when using blue Kessil irradiation reagent 1a was not totally consumed ( With a suitable set of conditions established, we turned our attention to evaluate the substrate scope of the oxidative hydroxytrifluoroethylation process with a range of commercially available styrenes (Table 2).In general, unsubstituted styrenes, as well as electron-rich and electron-poor groups tethered to the phenyl ring presented comparable reactivity.The reaction is tolerant toward esters, ethers, ketones, bromides, and several heterocycles.Electron-rich 4-substituted styrenes worked well under the optimized reaction conditions, providing the desired acetophenones in yields that ranged from 54 to 66% (3−7).Unsubstituted styrene and 2-vinylnaphthalene also demonstrated to be suitable substrates for this difunctionalization process (8−9).The ortho-and parasubstituted acetophenone 10 was isolated in a moderate 45% yield, while bulkier groups in ortho position (such as bromide substituent) were not well tolerated.Moreover, 3-fluorostyrene yielded the 2-hydroxytrifluoroethylacetophenone 11 in moderate yield.Of note, the structure of the synthesized products was demonstrated by single-crystal X-ray diffraction study of compound 11, where linked molecules pairs were found for an expected double hydrogen bond (Table S6 in the Supporting Information).Then, para-halogenated styrenes also showed likewise efficacy the unsubstituted or more electronically rich styrenes (12−14).Interestingly, complete retention of the bromide moiety (14) opens new opportunities for further functionalization.Interestingly, difunctionalization of indene and dialin fused rings provided the hydroxytrifluoroethylated carbonyls (15 and 16) in moderate yield and diastereomeric ratio.On the other hand, functionalization of disubstituted analogues such as (2-methylprop-1-en-1-yl)benzene did not proceed well.Heterocyclic compounds including benzothiophene (17 and 18) and benzofurane (19) skeletons were readily incorporated under the optimal reaction conditions.Next, we evaluated the amenability of this process to more architecturally complex alkenes derived from nonsteroidal antiinflammatory styrene derivatives like ibuprofen (20), fenbufen (21) or flurbiprofen (22).Our investigation revealed that these substrates can accommodate the hydroxytrifluoroethyl group in an efficient manner.Thus, we provide quick access to analogs of such structures with the pharmacologically relevant trifluoroethanol group.
Within the field of drug design, the difluoromethyl (−CF 2 H) group is recently earning considerable attention because it has been proved to be a more metabolically stable Table 1.Exploration of the Reaction Conditions a a Reaction conditions: 1a (0.2 mmol, 2 equiv), 2a (0.1 mmol, 1 equiv), photocatalysts (PC) (indicated amounts) in 0.5 mL of DMSO (c = 0.2 M) under violet Kessil lamp irradiation (λ max = 427 nm) at rt for 24 h.b Yields were determined by 1 H NMR analysis using 1,3,5trimethoxybenzene as internal standard.c Purple Kessil irradiation (λ max = 390 nm).The Journal of Organic Chemistry bioisostere of thiol and alcohol groups and a good lipophilic hydrogen bond donor. 20Despite the significance of this chemical space, the availability of bifunctional CF 2 H sources as effective reagents is limited. 21The bench-stable N-difluor-oethoxyphthalimide 1b was prepared 22 and tested in the difunctionalization process (Table 3).First, we detected that this reaction needed longer reaction time to be completed.In the crude 1 H NMR we were delighted to recognize good    The Journal of Organic Chemistry reactivity, however, degradation of the desired compound was observed upon purification by flash column chromatography leading to poor yields (see characterization of compound 26 in the Supporting Information).Given this experimental obstacle, we planned to reduce the carbonyl group in a two-step process to yield the corresponding diol.Following this strategy, reagent 1b provided the desired diols 23−25 from low to moderate yields (Table 3).Particularly, reagent 1b not only can be reduced by 4DPAIPN (E c = −1.67V vs Fc + /Fc, see Scheme 2A), but also the generated alkoxy radical undergoes 1,2-HAT event efficiently producing the desired difluoromethylene compounds.
Next, we probed the scalability of this protocol in a 2.5 mmol scale using 4-tert-butylstyrene as a model alkene and reagent 1a.The reaction scale was increased 5-fold in batch with comparable yield (Scheme 2B) obtaining 376 mg of 4.
We then endeavored to gain a deeper understanding of the mechanism of this difunctionalization process.We speculated that reagent 1a undergoes an irreversible and reductive SET process triggered by the PC to afford the radical ion intermediate, where the oxygen centered radical is then generated after mesolytic N−O bond fragmentation.This was experimentally supported by Stern−Volmer luminescence quenching studies.Mixtures of 4-acetoxystyrene model and 1a with 4DPAIPN revealed that the excited state of the photocatalyst is quenched most effectively by the fluorinated redox active species 1a rather than by olefinic substrate, with an observed constant K SV of 85.6 M −1 (Scheme 2C and Supporting Information).Next, a radical trapping experiment with TEMPO revealed the involvement of radical species during the mechanism (see Supporting Information) since no product was formed.
Based on these mechanistic findings, the electrochemical data and related literature, 13 a plausible mechanism is presented in Scheme 2D.Upon photoexcitation of 4DPAIPN under light irradiation (λ max = 427 nm), a highly reducing excited state *4DPAIPN is generated (E (PC+/ * ) = −1.99V vs Fc + /Fc, see Table S1 in the Supporting Information).Single electron transfer process to redox active species 1 (E a = −1.63V vs Fc + /Fc for 1a and E a = −1.67V vs Fc + /Fc for 1b) forms the reduced radical anion species A, which delivers the phthalimide anion and the oxygen-centered radical B via βscission.Then, we propose that C(sp 3 )-hybridized radical C is formed from B by intramolecular 1,2-hydrogen atom transfer (1,2-HAT) event promoted by DMSO (TS B−C in Scheme 2D). 13Subsequently, C undergoes Giese addition to vinyl The Journal of Organic Chemistry arene yielding a relatively stabilized secondary and benzylic radical D (E a = 0.37 V vs SCE). 23This open-shell intermediate is oxidized to carbocation E by PC + (E PC+/0 = 0.63 V vs Fc + / Fc), restoring the photocatalytic cycle.Subsequent transformation of intermediate E promoted by DMSO and phthalimide anion 17 provides access to 2-hydroxydifluoroand 2-hydroxytrifluoroethylacetophenones.

■ CONCLUSIONS
The presented synthetic method addresses a pressing demand in the synthesis of fluorinated small molecules.We are presenting the first incorporation of the hydroxytrifluoroethyl group into alkenes from the photochemical reduction of Ntrifluoroethoxyphthalimide.This difunctionalization process exploits the in situ generation of the key carbon-centered αhydroxy-α-trifluoroethyl radical facilitated by DMSO.Access to 2-hydroxytrifluoroethylacetophenones is expedited using the organic photoredox 4DPAIPN species and mild oxidation conditions.The synthesis of difluoromethylene analogues is also feasible under the reported conditions.This synthetic method is found to be suitable in the difunctionalization of simple and more complex styrenes and related heteroaromatics.Lastly, mechanistic experiments support the operation via net-neutral radical/polar crossover photoredox cycle.
■ EXPERIMENTAL SECTION General Information.All chemical transformations requiring inert atmosphere were done using Schlenk line techniques.For violet light irradiation, a Kessil PR160-violet LED lamp (30 W High Luminous DEX 2100 LED, λ max = 427 nm) was placed 4 cm away from the reaction vials.Photoinduced reactions were performed using 4 or 8 mL Chemglass vials (15−425 Green Open Top Cap, TFE Septa).Reactions were monitored by TLC or NMR.TLC analysis was performed using hexanes/EtOAc mixtures as the eluent unless specified and visualized using ultraviolet (UV) light and/or Vanillin solution.The cyclic voltammetry (CV) experiments were performed with a BioLogic SP-50 Single Channel Potentiostat in a onecompartment three-electrode setup using a glassy carbon disk as the working electrode (ø = 3 mm), platinum wire as the auxiliary electrode, and SCE or AgNO 3 /Ag (0.01 M AgNO 3 , 0.1 M [NBu 4 N]PF 6 (TBAPF 6 ), MeCN) as reference electrodes.CV were performed at room temperature using the appropriate solvent, degassing with argon for 60 s and using TBAPF 6 as supporting electrolyte (0.1 M).All the experiments were referred to ferrocene as an internal standard.Polishing of the working electrode has been done using an alumina polishing pad with a solution of 0.05 μm alumina in water (purchased from BAS INC.).NMR experiments ( 1 H, 13 C, 19 F) were performed in the Servei de Ressonaǹcia Magnetica Nuclear, UAB, using NEO 300, 400, 500, or 600 spectrometers.Chemical shifts are referenced to residual, nondeuterated CHCl 3 (δ 7.26 in 1 H NMR and 77.16 in 13 C NMR).The HRMS (ESI+) and elemental analyses were done by the Servei d'Analisi Qui ́mica of UAB and Parque Cienti ́fico Tecnoloǵico of UBU.HRMS determined by a Bruker microTOF-QII mass spectrometer (fly time analyzer) through positive electrospray ionization.IR spectra were recorded on an FT-IR PerkinElmer using either neat oil or solid products.Fluorescence measurements were obtained using septa-capped UV-Quartz cuvettes (10 mm path length) from Hellma Analytics and were recorded in a PerkinElmer LS 55 Fluorescence Spectrometer attached to a PTP 1 Peltier Temperature Programmer maintaining the temperature at 25 °C.Melting points (°C) are uncorrected.Deuterated NMR solvents were purchased from Eurisotop.Dry solvents were obtained from Aldrich or Fisher and used as received.Bulk DCM, EtOAc and hexane were purchased from VWR. Chemicals were purchased from Fluorochem and Merck and used as received unless specified.
General Procedure for the Photoinduced Synthesis of 2-Hydroxytrifluoroethylacetophenones (3−22).To a flame-dried 4 mL vial equipped with a magnetic stir bar, redox active ether 1a (245.0 mg, 1.0 mmol, 2.0 equiv), the corresponding styrene (0.5 mmol, 1.0 equiv) and 4DPAIPN (7.9 mg, 0.01 mmol, 0.02 equiv) were dissolved in 2.5 mL of dry DMSO.Afterward, the solution was degassed with Argon for 20 s.The reaction mixture was irradiated for 90 min with a 427 nm Kessil PR160-violet LED as described in the "Workflow" section described in the SI.The temperature of the reaction was maintained at approximately 25 °C via a fan.After the reaction time, the mixture was diluted with AcOEt (10 mL) and washed with brine (3 × 10 mL).The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.The crude mixture was purified by flash column chromatography.
Step 1: To a flame-dried 4 mL vial equipped with a magnetic stir bar, redox active ether 1b (227.0 mg, 1.0 mmol, 2.0 equiv), the corresponding styrene (0.5 mmol, 1.0 equiv) and 4DPAIPN (7.9 mg, 0.01 mmol, 0.02 equiv) were added, and the vial was subjected to 3 cycles of vacuum/argon degassing.Subsequently, 2.5 mL of dry DMSO was added under inert atmosphere and the solution was degassed with Argon for 30 s.The reaction mixture was irradiated for 16 h with a 427 nm Kessil PR160-violet LED as described in the "Workflow" section.The temperature of the reaction was maintained at approximately 25 °C via a fan.After the reaction time, the mixture was diluted with AcOEt (10 mL) and washed with brine (3 × 10 mL).The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.The crude mixture was used in the second step without further purification.
Step 2: Into a 5 mL round-bottom flask the crude mixture form Step 1 was dissolved in 0.6 mL of EtOH.Simultaneously, NaBH 4 (60.0 mg, 1.6 mmol, 12.8 equiv) was suspended in drops of H 2 O in an Erlenmeyer.Then, the suspension was slowly added to the initial mixture.The reaction is monitored by thin layer chromatography.Upon completion of the reaction, 5 mL of aqueous solution of NaOH 1 M was added to the mixture and then diluted with 5 mL of Et 2 O.The organic layer was separated and the aqueous layer was further extracted with Et 2 O (3 × 5 mL).The combined organic layer was dried over Na 2 SO 4 and evaporated under reduced pressure.The crude was purified by flash column chromatography through silica gel.

Table 2 .
Evaluation of Substrate Scope